Treatment of B-Cell Lymphoma

  • Michael Voulgarelis
  • Haralampos M. Moutsopoulos


Sjögren’s syndrome (SS) displays the highest incidence of malignant lymphoproliferative disorders among all of the autoimmune diseases. This association was highlighted in studies performed at the National Institutes of Health in the 1970s [1, 2] and verified in a meta-analysis that estimated the risk of Non-Hodgkin’s lymphoma (NHL) among the classic autoimmune diseases [3]. This meta-analysis reported that the possibility of an overt malignant lymphoproliferation is higher among SS patients (random effects standardized incidence rate (SIR) of 18.9 [95% confidence interval 9.4, 37.9]).


Marginal Zone International Prognostic Index Marginal Zone Lymphoma Extranodal Site Lymphoepithelial Lesion 
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37.1 Introduction

Sjögren’s syndrome (SS) displays the highest incidence of malignant lymphoproliferative disorders among all of the autoimmune diseases. This association was highlighted in studies performed at the National Institutes of Health in the 1970s [1, 2] and verified in a meta-analysis that estimated the risk of Non-Hodgkin’s lymphoma (NHL) among the classic autoimmune diseases [3]. This meta-analysis reported that the possibility of an overt malignant lymphoproliferation is higher among SS patients (random effects standardized incidence rate (SIR) of 18.9 [95% confidence interval 9.4, 37.9]). By comparison, the SIRs for lymphoma among patients with systemic lupus erythematosus and rheumatoid arthritis were 7.52 and 3.25, respectively [3]. Thus, along with Helicobacter pylori–positive gastric mucosa–associated lymphoid tissue (MALT) lymphomas, SS is a paradigm of antigen-driven lymphomatous evolution [4].

Clinical studies on SS-related lymphoma have been hampered by their relatively low incidence, the consequent challenges in performing large prospective studies, the lack of a universal approach to treatment, and by the absence of consensus in hematopathology with regard to nomenclature and classification. Despite these limitations, significant progress in the field has been recognized in recent years.

The life-time prevalence of NHL development in SS patients ranges between 5% and 10%, with the median age at lymphoma diagnosis being 58 years (range 33–82 years) and the median time from SS diagnosis to lymphoma evolution 7.5 years [1, 5, 6]. More than 98% of SS-associated lymphomas are of B-cell origin, of which 80% are low-grade lymphomas. These low-grade lymphomas include extranodal marginal zone (MZ) tumors of the MALT type (52.5%) and nodal MZ lymphomas (NMZL) (12.5%). Follicular and lymphoplasmacytic lymphomas occur much less commonly. High-grade, diffuse large B-cell lymphomas (DLBCL) account for 17.5% of lymphoma cases in SS [6].

In this review, we present current treatment approaches in patients with SS-associated B-cell NHLs and emphasize the need for tailored therapy according to the lymphoma subtype and patients’ individual clinical characteristics. We highlight recent advances in the natural history of SS-related lymphomas that influence therapeutic strategies, explore existing controversies in the field, and indicate areas that require additional investigation.

37.2 Marginal Zone (MZ) Lymphomas

The three major subtypes of MZ lymphomas are extranodal MZ B-cell lymphomas of the MALT type (MALT lymphoma), primary splenic lymphomas, and NMZL. Each of these MZ lymphoma types represents a clinically and prognostically unique subcategory within the present World Health Organization (WHO) classification [7]. MALT lymphomas represent the vast majority of MZ lymphomas, whereas the other two entities are relatively rare disorders. MALT lymphomas were named after the lymphoid micro-anatomic compartment that nourishes its presumed normal counterpart, the MZ. The MZ is situated around the follicular mantle at the periphery of the splenic white pulp, as well as at the periphery of lymphoid follicles (Fig. 37.1). The MZ fosters B-cell populations of varied maturation stages that, although functionally heterogeneous, share the capacities for plasma cell differentiation and homing to certain tissue compartments (Fig. 37.2).
Fig. 37.1

Splenic lymphoid follicle: Structure and elements. The lymphoid follicle has a pale-staining germinal centers (GC) in which B-cells are proliferating. Note the presence of a mantle zone (ManZ) that contains small lymphocytes and an outer marginal zone (MarZ) that contains larger lymphocytes that are less packed than cell in the ManZ. Outside the MarZ is the red pulp. MarZs are more evident in splenic follicles than lymph node follicles (H&E, ×  200)

Fig. 37.2

B-cell maturation in the peripheral lymph nodes. After leaving the bone marrow, the naive mature B-cells initially migrate to the outer region of the lymph node in the “primary” follicles to later transfer to the follicle mantles. Subsequently, these IgM+/IgD  +  cells come into contact with antigen and transform into proliferating extrafollicular B blasts, from which short-lived plasma cells and “primed” B-cells are derived. These “primed” B-cells stimulate and sustain the germinal center reaction, during which they transform into rapidly proliferating centroblasts. During the mitotic proliferation and differentiation of the centroblasts into centrocytes, somatic mutations in the variable region of the immunoglobulin genes emerge in a randomized manner. The centrocytes with mutations that lead to an increase in the affinity of the immunoglobulin receptor differentiate further, enabling them to pass out of the germinal center into the marginal zone to become long-lived plasma cells or “memory” B-cells. The long-lived plasma cells predominantly populate the bone marrow and organs that are directly exposed to foreign antigens (gastrointestinal tract). Memory IgM+CD27+ B-cells are the counterpart of MZ cells and possess preferential homing to mucosa-associated lymphoid tissue sites (Peyer’s patches, bronchus, larynx)

MZ lymphomas are the most common type of tumors encountered in SS patients [5, 6, 8]. According to one study, patients with SS exhibited a 28-fold higher risk of developing a MZ lymphoma compared with the general population [9]. Two recent, population-based Scandinavian studies reported a somewhat lower risk [9, 10].

37.2.1 Extranodal Marginal Zone Lymphomas of MALT Type

As a rule, MALT lymphomas are indolent. They are located at mucosal and non-mucosal extranodal sites that contain epithelium, usually columnar epithelium [11, 12]. The majority of these sites are normally devoid of any organized lymphoid element, but the neo-formation of an acquired MALT component, elicited by certain external antigenic challenges, precedes MALT lymphoma development. Although MALT lymphomas are pathogenetically associated with diverse stimuli such as infection (Helicobacter pylori) or autoimmune insults (Hashimoto thyroiditis), all appear to derive from neoplastic transformation of MZ B lymphocytes [13, 14, 15]. The histological features of MALT lymphoma closely simulate the original lymphoepithelial complexes of Peyer’s patches. Characteristic features include reactive lymphoid follicles, with or without colonization by neoplastic cells of MZ and/or monocytoid morphology (centrocyte-like cells) that infiltrate the overlying epithelium (lymphoepithelial lesions). These neoplastic cells are admixed with small B lymphocytes and plasma cells that may or may not be neoplastic [16] (Fig. 37.3).
Fig. 37.3

Lymphoepithelial lesions in MALT lymphoma of salivary gland. Centrocyte-like cells surround the salivary ducts and infiltrate the epithelium to form lymphoepithelial lesions (arrow). Within the lesions, the majority of the intraepithelial lymphocytes have a similar morphology to the neoplastic cells of the surrounding lymphomatous infiltrate. (H&E, ×  200). MALT mucosa-associated lymphoid tissue

Lymphoepithelial sialadenitis, the histologic hallmark of SS, is characterized by a lymphoid population that surrounds and infiltrates the salivary ducts. Lymphoepithelial lesions result from the disorganization and proliferation of ductal epithelial cells [17]. These lesions, which appear first as small clusters, progressively organize into lymphoid follicle-like structures that contain germinal centers. The phenotype of these immunocompetent cells, mainly primed CD4+ T lymphocytes, suggests the formation of activated follicular structures in which activated B-cells produce autoantibodies [18, 19, 20]. This MALT component, acquired ­secondarily to the autoimmune process, represents the substrate from which B-cell lymphomatous proliferation develops.

The distinction between lymphoepithelial sialadenitis with features of acquired MALT and MALT lymphoma remains both obscure and controversial, because clonally expanded populations of B-cells have been detected in both conditions. The distinction still relies upon the identification of particular morphological features. The presence of centrocyte-like, monocytoid and plasmacytoid cells that form broad halos around epithelial nests or broad strands and interconnect lymphoepithelial lesions are features consistent with a neoplastic process (Fig. 37.4). Other features indicating MALT lymphoma include the secondary infiltration of the reactive germinal centers by malignant lymphocytes, the presence of atypical plasma cells that contain Dutcher bodies (nuclear inclusions), clusters of histiocytes, and overt fibrosis. All the above, along with monoclonality confirmed by immunophenotyping, establish the MALT lymphoma diagnosis [17].
Fig. 37.4

Parotid MALT lymphoma in Sjögren’s syndrome. (a) Neoplastic marginal zone cells infiltrate around salivary duct remnants. The lymphoid cells form broad strands interconnecting lymphoepithelial lesions (H&E, ×  200) (arrow). (b) Atypical lymphoid cells diffusely positive for CD20 (immunostaining with L26 antibody ×  100). (c) In addition, there were about four times more lambda light-chain-positive plasma cells than kappa light-chain-positive cells

In SS patients, MZ lymphomas of the MALT type are primarily low-grade and localized (stage I and II) to extranodal areas [5] (Table 37.1). The salivary glands are the most commonly affected site, but other common extranodal sites are the stomach, nasopharynx, ocular adnexa, skin, liver, kidney, and lung. Twenty percent of patients display involvement of more than one extranodal site at diagnosis, illustrating the preferential migration of these cells to multiple mucosal sites. This fact emphasizes the importance of extensive staging procedures in SS patients with MALT lymphomas.
Table 37.1

Clinical characteristics of Sjögren’s syndrome patients with MALT lymphomas

Bulky Disease: Tumor mass size >7 cm

B symptoms: Unexplained weight loss of >10% of body weight in 6 months; unexplained, persistent or recurrent fever >38°C; recurrent drenching night sweats

IPI: International prognostic index. One point is assigned for each of the following parameters: Age greater than 60 years, stage III or IV, elevated serum LDH, ECOG/Zubrod performance status of 2, 3, or 4, and more than 1 extranodal site. The sum of the points allotted correlates with the following risk groups: Low risk (0–1 points), Low-intermediate risk (2 points), High-intermediate risk (3 points), and High risk (4–5 points)

Loco-regional lymph node involvement is common with MALT lymphomas, but generalized peripheral lymphadenopathy is extremely rare. Major salivary gland enlargement, particularly of both parotid glands, is the typical presenting symptom. Most patients display indolent disease with good performance status and the absence of B symptoms, splenomegaly, and bone marrow infiltration. Elevated levels of lactate dehydrogenase (LDH) or beta 2-microglobulin levels are unusual. SS patients with MALT lymphomas frequently also have concurrent vasculitis affecting the peripheral nerves, skin, and kidneys. Anemia, lymphopenia, paraproteinemia, and mixed monoclonal cryoglobulinemia (type II) contribute further to a distinctive clinical syndrome that is not encountered in MALT lymphomas that are unrelated to SS.

Regardless of the affected site at presentation, diagnostic studies should include the standard lymphoma staging procedures and the examination of Waldeyer’s ring with complete blood count; basic biochemical studies; serum protein electrophoresis; and assays for lactate dehydrogenase, beta 2-microglobulin, and cryoglobulins. Computed tomographic scans of the chest, abdomen, and pelvis are also appropriate, as is bone marrow biopsy (Table 37.2). The initial staging should include a gastroduodenal endoscopy with multiple biopsies from gastro-esophageal junction, each region of the stomach, and the duodenum. H. pylori infection also needs to be either confirmed or excluded. Fresh biopsy and washings material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry.
Table 37.2

Staging for MALT lymphoma in Sjögren’s syndrome


Physical examination

CT scan (neck, thorax, abdomen)

Laboratory tests

• Blood count

• LDH levels

• Immunofixation

• Liver and renal function

• HCV, HIV serology

• Cryoglobulins

• Functional thyroid tests

• C4 levels

• Albumin levels

• Beta-2 microglobulin

Bone marrow biopsy

Gastric endoscopy

Optionally, based on symptoms

• Endoscopic ultrasound

• Bronchoscopy and lavage

• Orbit MRI and ophthalmologic examination

Sites commonly involved by MALT lymphomas may require special diagnostic procedures. Ultrasonography and magnetic resonance imaging are useful for investigations of the thyroid, soft tissues (hard palate), salivary glands, and orbits. Primary bronchial mucosa–associated lymphoid tissue lymphoma requires histological assessment by bronchoscopy. Any pulmonary mass or pleural effusion detected should be examined histopathologically. The difficulty in staging MALT lymphoma lies in the application of traditional staging systems for nodal-type lymphoma in extranodal MALT lymphoma. The Ann Arbor system is based on the extension from contiguous nodes and can be misleading in MALT lymphomas, because the involvement of multiple extranodal sites may not reflect truly disseminated disease.

Several studies demonstrate that non-gastric MALT lymphomas in the general population have a good outcome [21, 22]. Five-year survival rates have ranged from 86 to 100%. Despite the fact that 30% of these patients present with disseminated disease, their outcome remains unaffected by the multi-focal nature of the lymphoma (5-year survival of 90%) [23]. Furthermore, none of the conventional oncologic approaches appear to influence the outcome of these patients. It has been suggested that chemotherapeutic intervention may be ineffective in preventing recurrence in the early stage of the disease [23].

Some patients with persistent disease can be allowed to go untreated for prolonged periods of time yet have normal life spans. A retrospective analysis by Ambrosetti et al. reported no significant differences in outcomes among SS patients with salivary MALT lymphomas who underwent no treatment or received a variety of treatment modalities, including surgery, radiotherapy, and chemotherapy [24]. This is consistent with a study conducted by our department, in which SS patients with salivary MALT lymphomas had a quite uncomplicated clinical course with a median overall survival of 6.4 years. Notably, at a median follow-up of 6 years, treated and untreated patients with MALT lymphomas showed the same overall survival [5]. Conversely, patients with nodal involvement or advanced disease, defined by concomitant nodal and extranodal and/or bone marrow infiltration, exhibit worse prognoses [23, 25].

The international prognostic index defines various risk groups according to clinical and laboratory parameters including age, stage, involvement of more than one extranodal site, lactate dehydrogenase level, and performance status. Patients determined to be at high risk of death by this index also have a poor prognosis [26].

The natural history of MALT lymphomas suggests a two-stage dissemination process. During the initial phase, the tumors spread to other MALT sites. In the second phase, the lymph nodes and bone marrow become affected [23]. Consequently, treatment should be “patient and case tailored,” taking into account the site and stage of the lymphoma along with the international prognostic index and clinical characteristics of the individual patient. In addition, bulky tumor, serologic markers such as elevated beta 2-microglobulin or reduced albumin levels, and the presence of a large-cell component in tissue histology at diagnosis are also linked to poor outcomes [26, 27].

37.2.2 Therapeutic Approaches of MALT Lymphomas

For SS patients with MALT lymphoma localized to the salivary glands or other regions (stage IE), a “wait and watch” policy is appropriate. Chemotherapy is reserved for patients with disseminated lymphoma that infiltrates multiple (not regional) lymph nodes and/or bone marrow, as well as for those who fall into the high-risk category according to the international prognosis index. This strategy may be especially appropriate for elderly patients who have asymptomatic disease, as well as for those with substantial comorbidities that preclude a vigorous therapeutic approach.

Alkylating agents (cyclophosphamide, chlorambucil), purine analogues (fludarabine, cladribine), and anti-CD20 monoclonal antibody therapy are all suitable options for disseminated disease, but these recommendations have not been substantiated by large patient series and randomized trials [28, 29, 30]. In patients with disseminated MALT lymphoma at presentation who do not have SS, single chemotherapeutic agents such as alkylating agents and nucleoside analogues achieve a 75% complete remission rate, with projected 5-year event-free and overall survival rates of 50% and 75%, respectively [28]. However, responses differ dramatically according to whether patients have gastric or non-gastric involvement of their MALT lymphomas; patients without gastric involvement fare substantially worse [30].

In a study conducted by our department, 75% of patients with SS-associated MALT lymphomas achieved complete responses following treatment with 2-chloro-2-deoxyadenosine [31]. OSS features, namely xerostomia, parotid gland enlargement, salivary flows, and hyposthenuria, also showed improvement, and the disappearance of cryoglobulins and monoclonal bands within the urine was also observed. In addition to its direct cytotoxic potential, 2-chloro-2-deoxyadenosine has been associated with a profound T-cell depletion. The potential implication of antigen-specific T-cells in MALT lymphoma pathogenesis explains the favorable effect of this agent in these lymphomas [32]. When considering this type of treatment, it is important to weigh the indolent nature of these malignancies against the potentially severe adverse effects that may accompany purine analogue administration.

Anti-CD20 monoclonal antibody strategies may also have a place in the management of MALT lymphoma. High response rates are particularly observed in untreated patients [29]. Preliminary studies have documented benefits of B-cell depletion with an anti-CD20 monoclonal antibody for the glandular and extraglandular manifestations of SS patients [33, 34, 35]. The overall response rate appears to be on the order of 75%. However, anti-CD20 treatments are not universally effective in SS patients with MALT lymphomas [36]. Responses may differ according to the particular tissues involved because this treatment may fail to eliminate distinct B-cell sub-populations, e.g., MZ cells. Anti-CD20 treatments may also be antagonized by microenvironmental factors that promote B-cell survival, as recently has been described in a murine model of SS [37, 38].

Recurrences of MALT lymphoma at the same or different nodal or extranodal sites have been reported in 25–35% of patients, even years after the achievement complete responses. This highlights the need for life-long follow-up [29]. The roles of higher doses of rituximab (or other B-cell depletion strategies), maintenance treatment, and combination therapy with conventional chemotherapeutic agents require further exploration. All of these approaches have proven beneficial in other types of lymphoma [39]. The combination of anti-CD20 monoclonal antibody administration with fludarabine or 2-chloro-2-deoxyadenosine has been reported to achieve a high complete response rate in both gastric and non-gastric MALT lymphomas [40, 41]. The concomitant use of an anti-CD20 monoclonal antibody with 2-chloro-2-deoxyadenosine increases the response rate and quality of response, significantly prolonging the time to treatment failure. In addition, an increased number of patients treated with this combination proved negative for minimal residual disease, which correlates with a longer time to treatment failure [41]. Figure 37.5 illustrates our algorithm for the management of MZ lymphomas in SS patients.
Fig. 37.5

Therapeutic guidelines for the management of SS-associated MZ lymphomas. No established guidelines have been developed for the treatment of extranodal salivary MALT lymphomas in SS patients. Our policy for the management of these lymphomas is presented in this figure. In localized disease, a wait and see policy is adopted with close follow-up. If lymphoma is disseminated with nodal and bone marrow involvement or the patients have several risk factors according to IPI, single agent chemotherapy such as chorambucil, 2cda, or rituximab is administered. Doxorubicin-based combined chemotherapy should be reserved for patients who have a high-grade transformation or high tumor burden as indicated by high LDH levels, a tumor mass greater than 7 cm, and bulky regional nodal involvement. In our experience, the use of R-CHOP regimen as a first-line treatment appears to be effective in SS patients with NMZLs

Prospective, multicenter, large series, randomized, double-blinded studies of SS patients with MALT lymphoma are needed to compare different chemotherapy regimens and determine the optimal approach for patients with disseminated or relapsing disease. Potentially active drugs could also include those that target the inhibition of the NFκB pathway, the downstream molecular product of the translocations involving MALT1 gene, such as bortezomid. The frequency of translocations ­involving MALT1 appears to be low in SS patients with non-gastric MALT lymphomas. In contrast, t(11;18)(q21;q21) which involves the MALT1 gene frequently occurs in patients with gastric MALT lymphoma and SS, which may explain, in part, why these patients are largely resistant to H. pylori eradication therapy [42]. Interestingly, the t(11;18)(q21;q21), specific to MALT-type lymphoma, is found in 18–24% of patients with gastric MALT lymphoma. In addition to antimicrobial therapy failure, this specific translocation is accompanied by a resistance to alkylating agents but is a marker for sensitivity to an anti-CD20 monoclonal antibody [43, 44, 45].

37.2.3 Nodal Marginal Zone B-Cell Lymphomas (NMZL): Histology, Differential Diagnosis, and Outcome

Patients with NMZL have worse outcomes compared to those with MALT lymphomas. The 5-year survival rates in NMZL range between 50% and 70% [46]. The survival curves for NMZL do not display any plateau, suggesting that disease is not with current treatments. The 5-year event-free survival is approximately 30%. The estimated median time to progression ranges between 1 and 2 years [47]. At diagnosis, 20% of patients have lymph node histology that reveals an increased percentage of large cells (>20%) and a high mitotic rate, indicating a transformation to diffuse large B-cell lymphoma [47].

More than two-thirds of SS patients with NMZL present with an advanced stage, displaying peripheral, abdominal nodal involvement and splenomegaly [6]. The nodal spread of MALT lymphoma in a patient with SS could resemble a NMZL, because the lymph node histologies in these conditions share several morphological features. However, isolated or disseminated lymphadenopathy in the absence of extranodal lesions should alert the clinician to the possibility of NMZL. NMZL may show different patterns of lymph node infiltration such as “marginal zone”-like/perifollicular, nodular, diffuse, or a combination of patterns [48] (Fig. 37.6). As a consequence, it is impossible to distinguish NMZL from MALT lymphoma by morphology or immunohistochemistry. Only thorough clinical staging can confirm a NMZL in the absence of concurrent extranodal involvement (Table 37.3).
Fig. 37.6

SS-associated nodal marginal zone B-cell lymphoma (NMZL). (a) Lymph node infiltration by NMZL is characterized by a predominant population of small- to medium-sized centrocyte-like, monocytoid B-cells and scattered transformed B-cells (H&E, ×  400). (b) Staining (anti-CD21  ×  200) for follicular dendritic cells (DDCs) reveals overrun follicles by showing residual meshwork of FDCs indicative of follicular colonization. The tumor cells surround reactive follicles and expand into the interfollicular areas. These results, together with the histological findings, confirmed that the lesion represented a B-cell marginal zone lymphoma. The clinical staging confirms the diagnosis of NMZL in the absence of extranodal involvement

Table 37.3

Clinical and histological features of 26 SS patients who developed marginal zone B-cell lymphoma


MALT (%) lymphoma

Nodal marginal zone lymphoma (%)


21/26 (80.8)

5/26 (19.2)





0 (0)


20 (95.2%)

5 (100)



Mean  ±  SD

50.71  ±  11.6

48  ±  9.4




Ann Arbor stage



16 (76.2)

1 (20)


5 (23.8)

4 (80)

Nodal involvement

3 (14.3)

5 (100)

Extranodal involvementa


1 (20)

Both nodal and extranodal

3 (14.3)

1 (20)

Bulky diseaseb

1 (4.8)

1 (20)


2 (9.5)

1 (20)


2 (9.5)

4 (80)

Bone marrow involvement

4 (19)

3 (60)

aParotid gland, submandibular salivary gland, lacrimal gland, lung

bTumor mass size >7 cm

cUnexplained weight loss of >10% of body weight in 6 months; unexplained, persistent or recurrent fever >38°C; recurrent, drenching night sweats

37.2.4 Managing NMZL

NMZLs resemble other primary nodal B-cell lymphomas such as follicular with respect to B symptoms, elevated serum concentrations of lactate dehydrogenase, performance status, and international prognosis index. NMZL represents a therapeutic dilemma because precise therapeutic guidelines do not exist, owing largely to the absence of data from studies with substantial numbers of cases. The current therapies for NMZL are heterogeneous and determined by the age of the patient and the clinical stage aggressiveness of the tumor. NMZL typically has a short time to progression. Feasible treatment options include polychemotherapy with anthracycline-based chemotherapy combined with an anti-CD20 monoclonal antibody. In our experience, the use of R-CHOP (a regimen comprising an anti-CD20 monoclonal antibody plus cyclophosphamide/doxorubicin/vincristine/prednisone) as a first-line treatment appears to be effective in SS patients with NMZL, although long-term results are still needed [49, 50, 51]. In young patients who experience disease relapses, autologous bone marrow transplantation should be considered [52].

37.3 Diffuse Large B-Cell Lymphomas

37.3.1 Histology and General Considerations

In some patients with SS, lymphomas tend to evolve toward less differentiated (higher grade) cell types [5]. The transition from benign chronic lymphoepithelial sialadenitis to indolent MALT lymphomas and possibly to high-grade lymphoma, e.g., DLBCL, represents a multi-step process caused by genetic alterations such as p53 allelic loss and mutations, hypermethylation of p15 and p16 genes, and p16 gene deletions [53, 54]. The histological transformation of MALT lymphoma to DLBCL is heralded by the emergence of an increased number of transformed blasts that form sheets or clusters, which eventually effaces the preceding MALT lymphoma (Fig. 37.7). It is unclear how many DLBCLs arise from preexisting MALT, nodal or follicular lymphomas. Immunohistochemical, karyotypic, and genotypic studies have provided convincing proof that the supervening large-cell lymphomas arise from the same clone as the low-grade lymphomas [53]. Thus, the majority of high-grade lymphomas in SS patients may represent blastic-variance of either MZ B-cell or follicular center cell lymphomas.
Fig. 37.7

Diffuse large B-cell lymphoma in Sjögren’s syndrome. Lymph node biopsy demonstrates a diffuse proliferation of large lymphoid cells that have totally effaced the architecture

SS patients with DLBCLs tend to be older than those with MALT lymphomas, with a median age at diagnosis of 58.4 versus 50.7 years respectively [6]. During transformation, the clinical picture is characterized by further nodal and extranodal dissemination [5]. The histologic transformation to high-grade lymphoma always denotes a poor prognosis. Consequently, it is crucial to identify de novo and secondary DLBCLs in SS patients since median overall survival is estimated at less than 2 years [5].

37.3.2 Treatment of DLBCL

Combined chemotherapy is recommended for patients with de novo or transformed DLBCL [50, 51]. A number of aggressive induction regimens have been used and evaluated in clinical studies, but large randomized trials have reported that the less aggressive classical CHOP chemotherapy (cyclophosphamide/doxorubicin/vincristine/prednisone) has comparable CR and overall survival rates. However, the median survival of SS patients with DLBCL treated with CHOP is estimated to be only 1.8 years [5]. The presence of B symptoms and a large tumor diameter (>7 cm) are independent death risk factors. In addition, CHOP therapy combined with an anti-CD20 monoclonal antibody (R-CHOP) has been shown to have a significant clinical effect in DLBCL among the general population, increasing both response rate and survival. These observations prompted us to use this regimen for the treatment of six SS patients with aggressive NHL [50, 51]. A major finding of our study was that R-CHOP induced sustained CR in all SS patients for a follow-up period of 2 years. Moreover, the extranodal manifestations of these patients, such as peripheral neuropathy and skin vasculitis, resolved after 8 cycles of R-CHOP. The remission of these symptoms and signs was accompanied by a decrease in the circulating mixed cryoglobulins as well as an increase in C4 complement component levels, indicating that this regimen effectively controls both the autoimmune and neoplastic process.

SS patients with unfavorable IPI score and involvement of more than one extranodal site are at a much higher risk of CNS disease, and should therefore be given CNS prophylaxis with intrathecal methotrexate injections [55]. Specific extranodal sites appear to be more frequently associated with CNS involvement, namely the testes, paranasal sinuses, hard palate, orbit, paravertebral masses, and bone marrow. Our observations warrant larger controlled trials to assess the effectiveness of this regimen.

37.4 Conclusions

SS-associated lymphomas are a heterogeneous group of malignancies. The most common subtype, accounting for up to 60% of lymphomas, is MZ lymphoma of MALT type. Recently, significant advances in our understanding of the morphology, phenotype, etiology, pathogenesis, and natural history, as well as the use of WHO classification of lymphoid neoplasms, have begun to elucidate the differences between MALT lymphoma and other lymphoproliferative disorders, enabling the identification of prognostic tissue markers. Beyond chemotherapy, a variety of new treatment options have emerged in the management of patients with SS MALT lymphoma, with B-cell depletion with monoclonal antibody therapy being the most significant. Nevertheless, the lack of large multicenter studies and the rarity of the disease prevent the proposal of a definite treatment approach.

Patients with low-grade lymphoma types, especially MALT lymphomas, including those with disseminated extranodal disease, should be managed conservatively with an anti-CD20 monoclonal antibody or other mild chemotherapeutic agents. In contrast, disease features that indicate high-grade disease are markers for poor prognosis. In patients who are otherwise young and fit, aggressive, multi-agent approaches to treatment may be indicated.


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Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  • Michael Voulgarelis
    • 1
  • Haralampos M. Moutsopoulos
    • 1
  1. 1.Department of Pathophysiology, School of MedicineNational University of AthensAthensGreece

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